ethyl 1-(2-chloroethyl)piperidine-4-carboxylate

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (199 g, for example, as prepared by Example 1) in water (800 ml) was added to toluene (2000 ml) and potassium carbonate (118 g) in water (800 ml) and rinsed in with water (400 ml). The mixture was stirred until a biphasic solution was obtained. The aqueous layer was separated and extracted with toluene (3000 ml). The combined organic layers were concentrated to 4000 ml by vacuum distillation. This solution was added to 0.5 M potassium hexamethyldisilazide in toluene (1700 ml) and toluene (2000 ml) at 40° C. Acetic acid (178 ml) was added, the mixture concentrated to 4000 ml by vacuum distillation and added to an 18% w/w aqueous potassium carbonate solution (2432 g). The layers were separated, the organic layer was concentrated to 3000 ml by vacuum distillation and toluene (1000 ml) added. The solution was cooled to −15° C. and 2M phenyl lithium in dibutyl ether (800 ml) added. Water (2000 ml) and n-butanol (700 ml) were added and the mixture heated to 75° C. The aqueous layer was removed and the organic layer washed with water (1000 ml). Toluene (1000 ml) was added and mixture distilled until 3000 ml of solvent had been removed, then cooled to 20° C. and stirred overnight. The product was filtered, washed with toluene (2×200 ml) and dried under vacuum at 40° C. to give a white solid (131 g, 57%). EI-MS m/z 294 (M+H+) Rt (3.6 min). rinsed in with water (400 ml) was obtained The aqueous layer was separated extracted with toluene (3000 ml) The combined organic layers were concentrated to 4000 ml by vacuum distillation This solution was added to 0.5 M potassium hexamethyldisilazide in toluene (1700 ml) and toluene (2000 ml) at 40° C Acetic acid (178 ml) was added the mixture concentrated to 4000 ml by vacuum distillation added to an 18% w/w aqueous potassium carbonate solution (2432 g) The layers were separated the organic layer was concentrated to 3000 ml by vacuum distillation and toluene (1000 ml) added 2M phenyl lithium in dibutyl ether (800 ml) added Water (2000 ml) and n-butanol (700 ml) were added the mixture heated to 75° C The aqueous layer was removed the organic layer washed with water (1000 ml) Toluene (1000 ml) was added mixture distilled until 3000 ml of solvent had been removed cooled to 20° C. stirred overnight The product was filtered washed with toluene (2×200 ml) dried under vacuum at 40° C.

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (199 g, for example, as prepared by Example 1) in water (800 ml) was added to toluene (2000 ml) and potassium carbonate (118 g) in water (800 ml) and rinsed in with water (400 ml). The mixture was stirred until a biphasic solution was obtained. The aqueous layer was separated and extracted with toluene (3000 ml). The combined organic layers were concentrated to 4000 ml by vacuum distillation. This solution was added to 0.5 M potassium hexamethyldisilazide in toluene (1700 ml) and toluene (2000 ml) at 40° C. Acetic acid (178 ml) was added, the mixture concentrated to 4000 ml by vacuum distillation and added to an 18% w/w aqueous potassium carbonate solution (2432 g). The layers were separated, the organic layer was concentrated to 3000 ml by vacuum distillation and toluene (1000 ml) added. The solution was cooled to −15° C. and 2M phenyl lithium in dibutyl ether (800 ml) added. Water (2000 ml) and n-butanol (700 ml) were added and the mixture heated to 75° C. The aqueous layer was removed and the organic layer washed with water (1000 ml). Toluene (1000 ml) was added and mixture distilled until 3000 ml of solvent had been removed, then cooled to 20° C. and stirred overnight. The product was filtered, washed with toluene (2×200 ml) and dried under vacuum at 40° C. to give a white solid (131 g, 57%). EI-MS m/z 294 (M+H+) Rt (3.6 min). rinsed in with water (400 ml) was obtained The aqueous layer was separated extracted with toluene (3000 ml) The combined organic layers were concentrated to 4000 ml by vacuum distillation This solution was added to 0.5 M potassium hexamethyldisilazide in toluene (1700 ml) and toluene (2000 ml) at 40° C Acetic acid (178 ml) was added the mixture concentrated to 4000 ml by vacuum distillation added to an 18% w/w aqueous potassium carbonate solution (2432 g) The layers were separated the organic layer was concentrated to 3000 ml by vacuum distillation and toluene (1000 ml) added 2M phenyl lithium in dibutyl ether (800 ml) added Water (2000 ml) and n-butanol (700 ml) were added the mixture heated to 75° C The aqueous layer was removed the organic layer washed with water (1000 ml) Toluene (1000 ml) was added mixture distilled until 3000 ml of solvent had been removed cooled to 20° C. stirred overnight The product was filtered washed with toluene (2×200 ml) dried under vacuum at 40° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (20.42 g, 92.9 mmol) in THF (600 mL) was cooled to −50° C. under Ar. LDA (2.0 M in heptane/THF/ethyl benzene, 70 mL, 140 mmol) was slowly added to the solution at −50° C. over 25 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) and extracted with Et2O (3×500 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The resulting orange oil was co-evaporated three times with DCM to remove excess ethyl benzene, resulting in the title compound (16.29 g, 95.7%). EI-MS m/z 184(M+H+) Rt (1.08 min). The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) extracted with Et2O (3×500 mL) The combined organic layers were dried over MgSO4 filtered concentrated under vacuum to remove excess ethyl benzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (20.42 g, 92.9 mmol) in THF (600 mL) was cooled to −50° C. under Ar. LDA (2.0 M in heptane/THF/ethyl benzene, 70 mL, 140 mmol) was slowly added to the solution at −50° C. over 25 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) and extracted with Et2O (3×500 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The resulting orange oil was co-evaporated three times with DCM to remove excess ethyl benzene, resulting in the title compound (16.29 g, 95.7%). EI-MS m/z 184(M+H+) Rt (1.08 min). The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) extracted with Et2O (3×500 mL) The combined organic layers were dried over MgSO4 filtered concentrated under vacuum to remove excess ethyl benzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl nipecotate (20.0 mL, 130 mmol) in acetone (180 mL) was added 1-bromo-2-chloroethane (21.6 mL, 260 mmol) followed by anhydrous K2CO3 (27.12 g, 196 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (75 mL) and extracted with Et2O. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum. Purification of the crude residue by flash chromatography (50% Et2O/50% hexane) on silica gel gave the title compound (10.99 g, 38.6%). EI-MS m/z 220(M+H+) Rt (1.20 min). concentrated under vacuum The resulting residue was treated with H2O (75 mL) extracted with Et2O The combined organic layers were dried with MgSO4 filtered concentrated under vacuum Purification of the crude residue by flash chromatography (50% Et2O/50% hexane) on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (20.42 g, 92.9 mmol) in THF (600 mL) was cooled to −50° C. under Ar. LDA (2.0 M in heptane/THF/ethyl benzene, 70 mL, 140 mmol) was slowly added to the solution at −50° C. over 25 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) and extracted with Et2O (3×500 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The resulting orange oil was co-evaporated three times with DCM to remove excess ethyl benzene, resulting in the title compound (16.29 g, 95.7%). EI-MS m/z 184 (M+H+) Rt (1.08 min). The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) extracted with Et2O (3×500 mL) The combined organic layers were dried over MgSO4 filtered concentrated under vacuum to remove excess ethyl benzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (20.42 g, 92.9 mmol) in THF (600 mL) was cooled to −50° C. under Ar. LDA (2.0 M in heptane/THF/ethyl benzene, 70 mL, 140 mmol) was slowly added to the solution at −50° C. over 25 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) and extracted with Et2O (3×500 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The resulting orange oil was co-evaporated three times with DCM to remove excess ethyl benzene, resulting in the title compound (16.29 g, 95.7%). EI-MS m/z 184 (M+H+) Rt (1.08 min). The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) extracted with Et2O (3×500 mL) The combined organic layers were dried over MgSO4 filtered concentrated under vacuum to remove excess ethyl benzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl nipecotate (20.0 mL, 130 mmol) in acetone (180 mL) was added 1-bromo-2-chloroethane (21.6 mL, 260 mmol) followed by anhydrous K2CO3 (27.12 g, 196 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (75 mL) and extracted with Et2O. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum. Purification of the crude residue by flash chromatography (50% Et2O/50% hexane) on silica gel gave the title compound (10.99 g, 38.6%). EI-MS m/z 220 (M+H+) Rt (1.20 min). concentrated under vacuum The resulting residue was treated with H2O (75 mL) extracted with Et2O The combined organic layers were dried with MgSO4 filtered concentrated under vacuum Purification of the crude residue by flash chromatography (50% Et2O/50% hexane) on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (20.42 g, 92.9 mmol) in THF (600 mL) was cooled to −50° C. under Ar. LDA (2.0 M in heptane/THF/ethyl benzene, 70 mL, 140 mmol) was slowly added to the solution at −50° C. over 25 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) and extracted with Et2O (3×500 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The resulting orange oil was co-evaporated three times with DCM to remove excess ethyl benzene, resulting in the title compound (16.29 g, 95.7%). EI-MS m/z 184 (M+H+) Rt (1.08 min). The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) extracted with Et2O (3×500 mL) The combined organic layers were dried over MgSO4 filtered concentrated under vacuum to remove excess ethyl benzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl nipecotate (20.0 mL, 130 mmol) in acetone (180 mL) was added 1-bromo-2-chloroethane (21.6 mL, 260 mmol) followed by anhydrous K2CO3 (27.12 g, 196 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (75 mL) and extracted with Et2O. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum. Purification of the crude residue by flash chromatography (50% Et2O/50% hexane) on silica gel gave the title compound (10.99 g, 38.6%). EI-MS m/z 220 (M+H+) Rt (1.20 min). concentrated under vacuum The resulting residue was treated with H2O (75 mL) extracted with Et2O The combined organic layers were dried with MgSO4 filtered concentrated under vacuum Purification of the crude residue by flash chromatography (50% Et2O/50% hexane) on silica gel

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate (20.42 g, 92.9 mmol) in THF (600 mL) was cooled to −50° C. under Ar. LDA (2.0 M in heptane/THF/ethyl benzene, 70 mL, 140 mmol) was slowly added to the solution at −50° C. over 25 min. The reaction was allowed to warm up to room temperature over 16 h. The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) and extracted with Et2O (3×500 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The resulting orange oil was co-evaporated three times with DCM to remove excess ethyl benzene, resulting in the title compound (16.29 g, 95.7%). ELMS m/z 184(M+H+) Rt (1.08 min). The reaction was quenched with K2CO3 (saturated aqueous) (500 mL) extracted with Et2O (3×500 mL) The combined organic layers were dried over MgSO4 filtered concentrated under vacuum to remove excess ethyl benzene

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl nipecotate (20.0 mL, 130 mmol) in acetone (180 mL) was added 1-bromo-2-chloroethane (21.6 mL, 260 mmol) followed by anhydrous K2CO3 (27.12 g, 196 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (75 mL) and extracted with Et2O. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum. Purification of the crude residue by flash chromatography (50% Et2O/50% hexane) on silica gel gave the title compound (10.99 g, 38.6%). ELMS m/z 220(M+H+) Rt (1.20 min). concentrated under vacuum The resulting residue was treated with H2O (75 mL) extracted with Et2O The combined organic layers were dried with MgSO4 filtered concentrated under vacuum Purification of the crude residue by flash chromatography (50% Et2O/50% hexane) on silica gel